The present invention relates generally to the use of porphyrins to detect lung cancer, and more particularly to the use of tetra-aryl porphyrins, of which 5,10,15,20-tetrakis(4-carboxyphenyl)porphine is an example, to detect and treat lung cancer. This invention is the result of Contract No. W-7405-ENG-36 between the Regents of the University of California and the U.S. Department of Energy.
Cancer of the lung is a major world health problem and remains untreatable. It has been determined that in 1986 malignant lesions of the lung killed more than three times as many men as cancer of the colon and surpassed breast cancer as the major lethal malignant disease in women. Despite an enormous commitment of resources during the past decade, the success in the management of lung cancer has been minimal at best. In fact, in 1988, the annual death rate for lung cancer in the United States was estimated to approach 110,000 deaths. In addition, 150,000 new cases of lung cancer were diagnosed in 1988, making lung cancer the number one cancer killer. Attempts at mass-screening high risk populations have also been unsuccessful.
The treatment of lung cancer has largely been unsuccessful and at times controversial. The overall five-year survival for a patient with lung cancer still remains less than 10%. The practice of surgically resecting the tumor is the most successful of all treatments; however, in most cases the malignant lesions recur or metastasize. The use of radiotherapy and chemotherapy have also had limited success in prolonging the life of lung cancer patients. In fact, the median survival for a patient with small cell lung carcinoma, who is treated with chemotherapy and with or without radiation therapy is 10-15 months in patients with "limited" disease, and 7-11 months in patients with "extensive" disease.
The association between lung cancer and cigarette smoke is well established; however, other environmental factors also play a role in the etiology of lung cancer. One of these environmental agents is radon-222, a noble gas that is ubiquitous in the natural environment and is created by the decay of radium, which is in turn derived from the decay of uranium. Uranium is present in the earth's crust throughout the world. Radon gas forms within the earth's surface during uranium decay and diffuses into the atmosphere, where it becomes a health hazard. When radon decays in the atmosphere, its short-lived radioactive daughters (isotopes of polonium, bismuth, and lead) attach themselves to dust particles in the air. These radioactive particles as well as unattached radon daughters are then inhaled into the lungs. Radon and radon daughters give off alpha, beta, and gamma radiation. It is estimated that radon daughters deliver over 95% of the alpha radiation dose to the basal cells in the tracheobronchial epithelium of the lung.
Epidemiologic evidence has determined that exposure to radon and its daughters results in an increased risk of bronchial carcinoma. In the early 1960's, cytological techniques were developed to detect lung cancer in uranium miners, who, through multiple processes, are exposed to significant radon and radon daughter inhalation applied to the bronchial epithelium over a period of many years. It has been demonstrated further that the incidence of lung cancer in miners who smoke cigarettes is ten times greater than miners who did not smoke. These pulmonary cytopathology techniques have proven to be a very sensitive procedure for detecting abnormal/cancerous cells in high risk populations, such as uranium miners; however, once neoplastic cells have been identified, the task of localizing the occult carcinoma in the lung can be difficult, and in many cases an impossible problem. Because most in situ lesions cannot be seen with the unaided eye, such lesions must be localized by selective bronchial brushing and blind spur biopsies. These diagnostic procedures require general anesthesia and at least 2-3 hours to perform. The location of such early neoplastic lesions is of significant importance for the treatment of lung cancer. It is believed by many that for the treatment of lung cancer to be successful, the treatment procedure must be started at an early stage of cancer development (in situ). To successfully detect these early malignant lung lesions, new compounds must be developed which can be used in routine clinical procedures to detect small lung lesions.
Porphyrins and, in particular, hematoporphyrin derivative have been known for many years to have a significant affinity for malignant cancer cells, and have been demonstrated to be useful as diagnostic markers. Tumor cells that have taken up hematoporphyrin fluoresce when illuminated with uv light. However, the specificity of uptake of the porphyrins used in the past has not been as complete as desirable; that is, there is a substantial background of fluorescence from noncancerous cells accompanying the fluorescence from the cells of interest. Hematoporphyrin derivative has been used more recently for the imaging of neoplastic invasion of the bladder in humans. The procedure involves endoscopic exploration of the suspected tumor site with instrumentation that will detect fluorescent emission arising from the excitation of porphyrins with 400 nm light.
Porphyrins have also been used in the diagnosis and localization of small radiologically occult lung tumors (D. A. Cortese et al., "Hematoporphyrin Derivative In The Detection And Localization Of Radiographically Occult Lung Cancer," Am. Rev. Respir Dis 126, 1087 (1982); H. Kato et al., "Early Detection Of Lung Cancer By Means Of Hematoporphyrin Derivative Fluorescence And Laser Photoradiation," Clin. Chest Med. 6, 237 (1985) In these studies, a photoelectric fluorescence detection system in combination with a conventional bronchoscope was used to identify and localize early squamous cell carcinomas in patients with normal chest radiographs. K. B. Patel et al., "Fluorescing Cells In Sputum After Parenteral HPD," in Progress In Clinical And Biological Research, Vol. 170, D. Doiron and C. Gomer, Eds.; "Porphyrin Localization And Treatment Of Tumors," pp. 521-530 (1984) have also demonstrated that malignant cells could be detected in sputum samples from lung cancer patients injected with hematoporphyrin derivative. In this study, malignant cells as well as some nonmalignant cells fluoresced up to 9 days following the intravenous injection of the porphyrin. The uptake of porphyrin in normal cells is not unusual because other tissues, such as embryonic and traumatized tissues have also been reported to localize hematoporphyrin derivative.
The localization of malignant lesions using the procedures described above is dependent upon the visual detection of the red fluorescent emission of the porphyrin. In most procedures, this is accomplished by scanning the lung with a bronchoscope adapted to emit light at a wavelength (400 nm ) which will excite the porphyrin molecules. The limiting factor with this procedure is that it is time consuming and requires highly trained personnel to examine all areas of the lung for malignant lesions. Because the fluorescent emission from these small lesions is so weak and difficult to observe, small lesions can easily be missed. In addition, to visually detect porphyrin fluorescence, the porphyrin must be on the surface of the tumor and the tumor must lie on the surface of the lung. Any material, such as mucous covering, or the situation where a tumor is deep-seated, interferes with the overlying detection of porphyrin fluorescence. As a result, porphyrins have not been used successfully as a diagnostic tool for occult lung lesions.
Accordingly, it is an object of our invention is to provide a method for selective irradiation of occult malignant tumor masses in the lungs of patients.
Additional objects, advantages, and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.